Chronic pain is typically managed with extended use of opioid analgesics, despite an absence of data on their long-term efficacy and clear evidence of significant health risks. Prolonged opioid use dysregulates the endogenous opioid system, disrupting hedonic homeostasis in the brain and resulting in hyperalgesia, stress reactivity, and reward insensitivity ? factors that exacerbate chronic pain and increase risk for opioid misuse. Thus, chronic pain patients receiving extended opioid therapy suffer from impaired regulation of aversive (e.g., pain) and appetitive experience (e.g., pleasure), dual processes subserved by opioid-mediated, hedonic regulatory mechanisms. However, according to a 2015 NIH systematic review, there are no interventions with proven efficacy for improving outcomes among chronic pain patients on long-term opioid therapy. Extant therapies may have limited efficacy because they fail to directly target the neural circuits of hedonic regulation. In contrast, meditation-based interventions, which have been conceptualized as means of self-regulating hedonic function, may hold promise for addressing this public health concern. The overarching aim of this proposal is to determine the capacity of a novel meditation intervention, Mindfulness-Oriented Recovery Enhancement (MORE), to restore endogenous opioid system function as measured with PET and a selective ?-opioid radiotracer. In the R61, we will compare the effects of MORE to a support group (SG) control on measures of endogenous opioid system function during sustained muscle pain, and will use fMRI and behavioral measures to assess whether changes in opioid function are associated with improved regulation of appetitive (reward) and aversive (pain) experience among chronic non-neuropathic back pain patients (CNBP). In the R33, we will further validate the opioid functional mechanism by examining the A118G allele of the ?-opioid receptor gene (which has been linked to low ?-opioid function, hyperalgesia, and insensitivity to opioid analgesia) as a moderator of MORE?s effects on the endogenous opioid system, fMRI measures of natural reward responsiveness, and clinical outcomes ? including pain and opioid use. Furthermore, to refine our understanding of how the intervention modulates these neural mechanisms, the R33 will assess the dose of meditation skill practice as a predictor of changes in endogenous opioid function and clinical correlates. This multi-PI proposal unites expertise in meditation-based interventions with expertise in neurogenetics and the use of PET and fMRI to probe the neurobiological mechanisms of pain and affective experience, and builds upon a program of prior research which provided preliminary efficacy data on the MORE intervention and standardized its delivery via manualization of the treatment and development of fidelity measures. By elucidating a key mechanism of this meditation-based intervention, the proposed translational research will enable rapid optimization of MORE for Stage III clinical trial implementation and dissemination, allowing us to provide a timely solution to this public health problem of escalating significance.